CN102414216B - Novel stable crystal of 1-(2'-cyano-2'-deoxy-ss-d-arabinofuranosyl)cytosine monohydrochloride - Google Patents
Novel stable crystal of 1-(2'-cyano-2'-deoxy-ss-d-arabinofuranosyl)cytosine monohydrochloride Download PDFInfo
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- CN102414216B CN102414216B CN201080017920.4A CN201080017920A CN102414216B CN 102414216 B CN102414216 B CN 102414216B CN 201080017920 A CN201080017920 A CN 201080017920A CN 102414216 B CN102414216 B CN 102414216B
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- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 title claims abstract description 118
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 229940104302 cytosine Drugs 0.000 title claims abstract description 32
- 239000013078 crystal Substances 0.000 title abstract description 9
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 15
- 238000002425 crystallisation Methods 0.000 claims description 129
- 230000008025 crystallization Effects 0.000 claims description 129
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- 125000003147 glycosyl group Chemical group 0.000 claims description 29
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 239000000843 powder Substances 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- 229940034982 antineoplastic agent Drugs 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000006166 lysate Substances 0.000 claims description 2
- 230000008018 melting Effects 0.000 abstract 1
- 238000002844 melting Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 35
- 239000002904 solvent Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
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- 238000006243 chemical reaction Methods 0.000 description 6
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- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
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- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
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- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- VAVNRUJMHSTYME-NZZKMWLNSA-N NC(C=CN1[C@@H](C2C#N)O[C@H](CO)C2O)=NC1O Chemical compound NC(C=CN1[C@@H](C2C#N)O[C@H](CO)C2O)=NC1O VAVNRUJMHSTYME-NZZKMWLNSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 190000008236 carboplatin Chemical compound 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
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- 238000011835 investigation Methods 0.000 description 1
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
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- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 108010001062 polysaccharide-K Proteins 0.000 description 1
- MREOOEFUTWFQOC-UHFFFAOYSA-M potassium;5-chloro-4-hydroxy-1h-pyridin-2-one;4,6-dioxo-1h-1,3,5-triazine-2-carboxylate;5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione Chemical compound [K+].OC1=CC(=O)NC=C1Cl.[O-]C(=O)C1=NC(=O)NC(=O)N1.O=C1NC(=O)C(F)=CN1C1OCCC1 MREOOEFUTWFQOC-UHFFFAOYSA-M 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
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- 238000010254 subcutaneous injection Methods 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
Disclosed is a stable crystal of 1-(2'-cyano-2'-deoxy-beta-D-arabinofuranosyl)cytosine monohydrochloride. The crystal of 1-(2'-cyano-2'-deoxy-beta-D-arabinofuranosyl)cytosine monohydrochloride shows characteristic peaks at 13.7 DEG , 15.7 DEG , 16.0 DEG , 18.6 DEG , 20.3 DEG , and 22.7 DEG as diffraction angles (2theta +- 0.1 DEG ) by powder X-ray diffractometry and has a melting point of 192 to 197 DEG C.
Description
Technical field
The present invention relates to the stable form crystallization as the useful 1-of the medicine with excellent anti-tumor activity (2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride and the medical composition containing it.
background technology
Generally speaking, when the effective active composition as pharmaceuticals uses compound, in order to stably keep quality and/or in order to easily carry out keeping management, need the chemistry of compound and the stability of physics.Therefore, the compound of gained is preferably stable form crystallization, usually, as the former medicine of pharmaceuticals, is select most stable form crystallization mostly.
In patent documentation 1, non-patent literature 1 and non-patent literature 2, as one of Pyrmidine nucleoside derivatives, describe 1-(2 '-cyano group-2'-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride shown in following formula (1), there is the effect of the tumor cell proliferation suppressing people or mouse in vitro, also there is excellent anti-tumor activity in vivo.
As its manufacture method, report 1-(2 '-cyano group-2'-deoxidation-β-D-arabinofuranosidase glycosyl)-N shown in following formula (2)
4-ethanoyl cytosine(Cyt) is dissolved in the methanol solution of hydrochloric acid, reacts while stirring in room temperature, is made the method (non-patent literature 1 and 2) of its crystallization after reaction terminates by ethanol and ether; And after the compound acetic acid reflux shown in following formula (2) is carried out the process of de-N-ethanoyl; pass through silica gel column chromatography; obtain 1-shown in following formula (3) (2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt); by this compound dissolution in the methanol solution of hydrochloric acid; react while stirring in room temperature, after reaction terminates, made the method (patent documentation 1) of its crystallization by ethanol and ether.
The crystallization obtained by these methods, had been made for 1/2 ethanolates at that time, and its fusing point is 175 ~ 176 DEG C (patent documentation 1 and non-patent literatures 1 ~ 2).But, except this fusing point, there is no the concrete report about its polymorphic or stability.
Prior art document
Patent documentation
Patent documentation 1: Japanese Patent No. 2559917 publication (Unexamined Patent 4-235182 publication)
Non-patent literature
Non-patent literature 1:Journal of Medicinal Chemistry, 1991,34 volumes, 2917-2919
Non-patent literature 2:Journal of Medicinal Chemistry, 1993,36 volumes, 4183-4189
Summary of the invention
Invent problem to be solved
The object of the present invention is to provide a kind of stable form crystallization of the compound useful as antineoplastic agent.
For solving the method for problem
The present inventor is to obtain the stable form crystallization of 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride for problem, first attempt the known method recorded by above-mentioned patent documentation 1 and non-patent literature 1 ~ 2, obtain the crystallization of 1/2 ethanolates of fusing point 175 ~ 176 DEG C.
But be all beyond one's expectations, the present inventor could not reproduce the crystallization of 1/2 ethanolates of the fusing point 175 ~ 176 DEG C that document is recorded (hereinafter also referred to as " crystallization of known document " in the reproduction experiments of above-mentioned known method.)。
Further, the present inventor is in order to obtain the crystallization of 1/2 ethanolates of above-mentioned fusing point 175 ~ 176 DEG C, consider and the manufacturing condition deeply implementing various general crystallization (with reference to International Journal of Pharmaceutics, nineteen ninety, 60 volumes, 11-26 etc.), but finally also could not reproduce the crystallization of known document.
Therefore, like this consider the also unavailable crystallization of various manufacturing condition even if can think, as can industrially stablize manufacture, the crystallization that supplies can not be called preferred crystallization.As such reason, the crystallization of gained at that time may be polymorphic, under confirming that the former medicine of pharmaceuticals exists polymorphous situation, usual existence becomes not easily as single crystallization or existence than the stable manufacture of the crystallization of the mixed type be managed as certain value, thus needs the problem of further investigation.
Past also reported the crystallization that in the past obtained with a certain period for boundary is by the unexpected unavailable example of prior art in paper.Such as, there is the ritonavir (Ritonavir) as AntiHIV1 RT activity (human immunodeficiency virus) medicine, due to emergent as the type II of stable form crystallization, record (the Organic Process Research & Development of the type I in the past existed is can not get by existing manufacture method, 2000,4 volumes, 413-417).Having the compound as cephalosporin analog antibiotic exploitation, be also because the emergent γ as stable form crystallization is brilliant, and the α in the past existed is brilliant in the unavailable record of existing manufacture method (isolation technique, the 33rd volume, 379-385 in 2003).There is the compound as the exploitation of HIV1-RT inhibitor, also be as the type III of stable form crystallization due to emergent, and record (the Organic Process Research & Development of the type I in the past existed is can not get by existing manufacture method, 2005,9 volumes, 933-942).
Comprehensively such opinion, can think the crystallization of the known document obtained at that time lower than crystallization of the present invention in stability, so can not get.In addition, even if can think that the crystallization of known document temporarily generates in reaction system, also carry out crystal type transfer to stable form crystallization immediately, result also can not get.
The present inventor in this study, as shown in embodiment described later, obtain not containing ethanol, fusing point is (following than the crystallization of high 15 ~ 20 DEG C of the known crystallization of fusing point 175 ~ 176 DEG C in the past, also referred to as " crystallization of the present invention "), because the fusing point of the generally speaking crystallization (stable form crystallization) of excellent in stability is higher than the fusing point of unstable crystallization (crystallization of quasi-steady type), so find that crystallization of the present invention is stable form crystallization, thus complete the present invention.
That is, the present invention is the content that following (1) ~ (4) relate to.
(1) crystallization of a kind of 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride, it is as the diffraction angle recorded by powder x-ray diffraction (2 θ ± 0.1 °), confirm characteristic peaks 13.7 °, 15.7 °, 16.0 °, 18.6 °, 20.3 ° and 22.7 °, fusing point is 192 ~ 197 DEG C.
(2) crystallization of a kind of 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride, it is as the diffraction angle recorded by powder x-ray diffraction (2 θ ± 0.1 °), confirm characteristic peak 6.4 °, 12.6 °, 17.3 ° and 21.7 °, fusing point is 192 ~ 197 DEG C.
(3) medical composition containing the crystallization described in above-mentioned (1) or (2).
(4) antineoplastic agent containing the crystallization described in above-mentioned (1) or (2).
The effect of invention
The crystallization of 1-of the present invention (2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride has excellent physical stability and/or chemical stability, therefore, such as from storage stability, purity, the viewpoint of operability (lower water absorbability) and/or qualitative control etc. is set out, in addition, from the view point of useful as antineoplastic agent because having excellent antitumous effect, be better than other amorphousness form or other the crystal habit etc. of 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt), useful as pharmaceuticals.
Accompanying drawing explanation
Fig. 1 represents the x-ray diffractogram of powder of I type crystallization.
Fig. 2 represents the x-ray diffractogram of powder of II type crystallization.
Fig. 3 represents the x-ray diffractogram of powder of type III crystallization.
Embodiment
Crystallization of the present invention, these 3 kinds of crystallizations of particularly I type crystallization, the crystallization of II type and type III crystallization, can by from containing 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride shown in above-mentioned formula (1) (below, also referred to as " compound (1) ") solution crystallization or recrystallize, obtain respectively as single crystallization.
In addition, the form of compound (1) can not be crystalloid, but also can be crystallization.When for crystallization, such as, also the crystallization of II type can be separated out the crystallization of I type as raw material, or separate out the crystallization of I type using type III crystallization as raw material.
The 1-that uses in the present invention (2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride (compound (1)), can by 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase the glycosyl)-N shown in above-mentioned formula (2)
4-ethanoyl cytosine(Cyt) is (following; also referred to as " compound (2) ") or 1-shown in above-mentioned formula (3) (2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) (following; also referred to as " compound (3) ") as raw material; obtained by organic chemical synthesis method; such as; can by compound (2) is taken off N-acetylize and addition hydrochloric acid, or pass through compound (3) addition hydrochloric acid to obtain.
As the more concrete method obtaining compound (1), can enumerate and acid treatment is carried out to compound (2) and obtains compound (3), its addition hydrochloric acid be obtained the method for compound (1); Use methanol hydrochloride solution to carry out acid treatment and hydrochloric acid addition with an operation to compound (2), thus obtain the method etc. of compound (1).
Wherein, from the view point of raising operation efficiency and raising yield, preferably carry out acid treatment and hydrochloric acid addition with an operation, as condition now, preferably relative to compound (2) 100mg, use the methanol hydrochloride solution 1 ~ 20mL of 0.5 ~ 3%, stir 0.5 ~ 3 hour (preferably 1 ± 0.25 hour) about 10 ~ 40 DEG C (preferred room temperatures).
Compound (2) and (3) can by the manufacture method manufactures described in above-mentioned patent documentation 1 and non-patent literature 1 ~ 2.
In addition, as acid-treated acid, the mineral acid such as sulfuric acid, hydrochloric acid can be enumerated; The organic acid such as acetic acid, trifluoroacetic acid, these acid can be used alone or mix two or more use.
As the method separating out crystallization of the present invention, be not particularly limited, but it is (following to enumerate the solvent making it be dissolved in solubilized above-claimed cpd (1) in a heated state, also referred to as " dissolution solvent ") in, the method for crystallization is made by being placed by the solution being dissolved with this compound (1) or utilize refrigerating unit to cool; Utilize the solvent to this compound (1) solvability is low (following, also referred to as " low-solubility solvent "), (following from this solution dissolved, also referred to as " solvent soln ") make the method etc. of crystallization, but wherein, preferably utilize low-solubility solvent to make the method for crystallization from this solvent soln.As an example of the method, the method etc. that the low-solubility solvent adding cooling in this solvent soln makes crystallization can be set forth in.
As the solvent used in crystallization operation, be not particularly limited, but can water be enumerated; The alcohols such as methyl alcohol, ethanol, Virahol; The ketone such as acetone, methylethylketone; The ethers etc. such as diethyl ether, diisopropyl ether, t-butyl methyl ether.These solvents can be used alone or use as multiple mixed solvent.
As above-mentioned dissolution solvent, preferably can make the solvent that compound (1) dissolves in a heated state, specifically, from the aspect of stability, alcohols is more preferred, wherein, and the alcohols of preferred carbonatoms 1 ~ 5, particularly preferably ethanol.The temperature of the dissolution solvent of heated condition is preferably the boiling point of 0 DEG C ~ solvent usually, is more preferably 20 ~ 40 DEG C.The concentration of this compound (1) is now not particularly limited, but is preferably 0.25 ~ 0.6 (W/V) % in solvent soln.
As above-mentioned low-solubility solvent, preferably adding to after in the solution having dissolved compound (1), by placing or cool the solvent that can make crystallization, specifically, from the aspect of stability, preferred ethers, wherein, particularly preferably diethyl ether.
The temperature of low-solubility solvent when adding this solvent soln is preferably-40 DEG C ~ boiling point that dissolves, is more preferably-20 ~ 20 DEG C, is more preferably 0 ~ 10 DEG C.The temperature of the solvent soln when adding the low-solubility solvent of the opposing party to is preferably the boiling point of-20 DEG C ~ dissolving, is more preferably-5 ~ 45 DEG C, is more preferably 0 ~ 40 DEG C.
In addition, the usage quantity of low-solubility solvent is preferably 0 ~ 1 capacity part relative to solvent soln 1 capacity part.
Temperature during precipitation is preferably-50 ~ 30 DEG C usually, is more preferably-40 ~ 20 DEG C, is more preferably-30 ~ 10 DEG C.Now, also can with the mixing solutions of refrigerating unit hot-cold lysis solution or itself and low-solubility solvent.Such as, can be set forth in the container of cooling and drip solvent soln; Solvent soln or its mixing solutions are cooled etc.During this precipitation, can place and also can stir this solution.
The crystallization of separating out, such as, can by filtering, with known separation purification method such as organic solvent cleaning, drying under reduced pressure, separation and purification from above-mentioned solvent soln or mixing solutions.As the organic solvent used in cleaning, above-mentioned low-solubility solvent can be enumerated, wherein, preferably use above-mentioned ethers.
Such operation can manufacture crystallization of the present invention, particularly I type crystallization, the crystallization of II type or type III crystallization.
Such as, as the method obtaining the crystallization of I type, preferably heating for dissolving compound (1) in ethanol, then, by this lysate is added drop-wise to be cooled to 0 ± 5 DEG C diethyl ether in while stir and obtain.
In addition, as the method obtaining the crystallization of II type, preferably heating for dissolving compound (1) or the crystallization of I type in ethanol, then, after this solution is cooled to 40 ± 5 DEG C, stirs by dripping diethyl ether and obtains.
In addition, as the method obtaining type III crystallization, preferably heating for dissolving compound (1) or the crystallization of I type in ethanol, then, by this solution is added drop-wise to be cooled to 0 ± 5 DEG C dish in and obtain.
I ~ type III the crystallization of the compound (1) that such operation obtains all has the fusing point of 192 ~ 197 DEG C, but as shown in the x-ray diffractogram of powder of Fig. 1 ~ 3, can by following characteristic diffraction peak identification.
Namely, the x-ray diffractogram of powder of I type crystallization, as shown in Figure 1, as the diffraction angle recorded by powder x-ray diffraction (2 θ ± 0.1 °), near 13.7 °, 15.7 °, 16.0 °, 18.6 °, 20.3 ° and 22.7 °, characteristic peak is confirmed.
In addition, the x-ray diffractogram of powder of II type crystallization, as shown in Figure 2, as the diffraction angle recorded by powder x-ray diffraction (2 θ ± 0.1 °), confirms characteristic peak near 6.4 °, 12.6 °, 17.3 ° and 21.7 °.
In addition, the x-ray diffractogram of powder of type III crystallization, as shown in Figure 3, as the diffraction angle recorded by powder x-ray diffraction (2 θ ± 0.1 °), confirms characteristic peak near 14.2 °, 16.4 °, 17.0 °, 18.0 ° and 20.2 °.
Crystallization of the present invention is that storage stability is very high, also favourable in qualitative control, the crystallization that operability is also excellent.Particularly as shown in following embodiment, even if the crystallization of I type is taken care of for a long time under hot and humid condition, total its related substances is not almost had yet, and do not observe crystal type change, in addition, from by near 70 ~ 90 DEG C, heat a few hours or near 30 ~ 50 DEG C and more than 75%RH preserve 1 month for a long time, the crystallization of II type or type III crystallization conversion are I type, and the crystallization of I type is also than the excellent in stability of the crystallization of II type or type III crystallization.
And from the record of above-mentioned patent documentation 1, above-claimed cpd (1) has very strong anti-tumor activity, therefore, medical composition containing crystallization of the present invention particularly can use as antineoplastic agent, in addition, can be used in manufacturing said preparation.
Crystallization of the present invention, particularly as each crystal habit of I type, II type or type III, the purity of preferred I type, II type or type III crystallization is essentially more than 95%, is preferably essentially more than 98%, is more preferably essentially more than 99%.
Crystallization of the present invention, pulverizes or does not pulverize, can be processed as the antineoplastic agent of various form, the oral preparation such as such as tablet, capsule, granule, granula subtilis, powder, syrup; Parenteral dose of intravenous injection, subcutaneous injection, intramuscular injection, suppository etc. etc.Crystallization of the present invention is intravenous administration, and its formulation is preferably injection, and this injection is expected as the solid injection agent of its freeze drying injection dissolving use or injectable powder etc. can be made in use to use.
Antineoplastic agent can use pharmaceutically acceptable carrier by usual formulation method manufacture as well known to those skilled in the art.Now, also can with other antineoplastic agent, such as 5-FU, UFT preparation, Tegafur-gimeracil-Oteracil Potassium preparation, Zorubicin, epirubicin, U 101440E, Etoposide, docetaxel, taxol, cis-platinum, carboplatin, oxaliplatin, krestin, lentinan, Picibanil (Picibanil) etc. are also used.
The dosage of the crystallization of the present invention when using as antineoplastic agent, although according to should use its patient symptom or its formulation etc. and might not, generally speaking, preferred every day will with crystallization gauge of the present invention 2.0 ~ 4.0mg/m
2be divided into 1 time or administration for several times.
Embodiment
Below, enumerate embodiment and reference example, specifically describe manufacture method of the present invention.
Reference example 1 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl)-N
4the synthesis of-ethanoyl cytosine(Cyt)
At N
4-ethanoyl-2 '-cyano group-2 '-deoxidation-3 '; 5 '-O-(1; 1; 3; 3-tetra isopropyl disiloxane-1,3-bis-base)-1-β-D-arabino-furanosylcytosine (537mg, 1mmol) THF (5mL) solution in; add 1M tetrabutylammonium THF solution (2mL), acetic acid 0.06mL (1mmol), stirring at room temperature 15 minutes.Concentrated after stirring, residue 8% ethanol-chloroform is column chromatography eluting by silica gel (11g) as developing solvent.With the concentrated residue of hexane-diethyl ether cleaning object composition, obtain the tagged compound 259mg (yield: 88%) as white crystals.
The synthesis of embodiment 1 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride
Dissolve 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl)-N in 1% hydrochloric acid methanol (7.5mL)
4-ethanoyl cytosine(Cyt) (100mg, 0.34mmol), stirs 1 hour in room temperature (20 ~ 25 DEG C).Concentration of reaction solution, injects ethanol (10mL) and makes it coevaporation, obtain tagged compound 34mg in this enriched material.(yield: 35%)
Fusing point: 192 DEG C
Ultimate analysis:
Calculated value is (as C
10h
13clN
4o
4): C, 41.60; H, 4.54; N, 19.41
Measured value: C, 41.45; H, 4.52; N, 19.41
The manufacture of the I type crystallization of embodiment 2 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride
By the 1-of embodiment 1 gained (2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride (200mg) reflux dissolving in ethanol (34mL), be added drop-wise in the diethyl ether (34mL) being cooled to 0 DEG C.Stir after 2 hours, leaching precipitate, at 35 DEG C of drying under reduced pressure, obtain the 123mg (yield: tagged compound 62%) as the crystallization of I type.
Fusing point (decomposition point): 192 ~ 197 DEG C
Ultimate analysis:
Calculated value is (as C
10h
13clN
4o
4): C, 41.60; H, 4.54; N, 19.41
Measured value: C, 41.64; H, 4.51; N, 19.28
The x-ray diffractogram of powder of the I type crystallization obtained is represented here in Fig. 1.As the diffraction angle recorded by powder x-ray diffraction (2 θ ± 0.1 °), near 13.7 °, 15.7 °, 16.0 °, 18.6 °, 20.3 ° and 22.7 °, confirm characteristic peak.
In addition, powder x-ray diffraction data, the X-ray diffraction device PW3050 manufactured by PHILIPS Co. irradiates CuK α line
vertical goniometer is used to detect.
The manufacture of the II type crystallization of embodiment 3 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride
By the I type crystallization (200mg) of 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride reflux dissolving in ethanol (34mL), after being cooled to 40 DEG C, while drip the ethanol (34mL) having dissolved this compound, be injected in the diethyl ether (34mL) of reflux state (being heated to the reaction vessel of 40 DEG C).After backflow limit, limit stirs 1 hour, the precipitate in leaching diethyl ether, at 35 DEG C of drying under reduced pressure, obtains the 119mg (yield: tagged compound 60%) as the crystallization of II type.
The x-ray diffractogram of powder of the II type crystallization obtained is represented here in Fig. 2.Use powder x-ray diffraction device to measure this II type crystallization as described above, as the diffraction angle recorded by powder x-ray diffraction (2 θ ± 0.1 °), near 6.4 °, 12.6 °, 17.3 ° and 21.7 °, confirm characteristic peak.
Fusing point (decomposition point): 192 ~ 196 DEG C
Ultimate analysis:
Calculated value is (as C
10h
13clN
4o
4): C, 41.60; H, 4.54; N, 19.41
Measured value: C, 41.48; H, 4.57; N, 19.14
The manufacture of the type III crystallization of embodiment 4 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride
By the I type crystallization (200mg) of 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride reflux dissolving in ethanol (34mL), in the container being cooled to 0 DEG C, slowly drip the solution of gained.Stir after 2 hours, leaching precipitate, at 35 DEG C of drying under reduced pressure, obtain the 66mg (yield: tagged compound 33%) as type III crystallization.
The x-ray diffractogram of powder obtaining type III crystallization is here represented in Fig. 3.Powder x-ray diffraction device is used to measure this type III crystallization as described above, as the diffraction angle recorded by powder x-ray diffraction (2 θ ± 0.1 °), near 14.2 °, 16.4 °, 17.0 °, 18.0 ° and 20.2 °, confirm characteristic peak.
Fusing point (decomposition point): 195 DEG C
Ultimate analysis:
Calculated value is (as C
10h
13clN
4o
4): C, 41.60; H, 4.54; N, 19.41
Measured value: C, 41.59; H, 4.42; N, 19.29
Embodiment 5 stability test
Uniformly dispersing I type and II type crystalline powder on the shallow chassis of glass system, cover the aluminium foil (being only the transparent resin made membrane that conditions of exposure is preserved) that appropriateness has opened ventilating pit, prepared testing inspection body.Respectively under 4 conditions of [60 DEG C], [40 DEG C/relative humidity (RH) 75%], [25 DEG C/relative humidity (RH) 60%/exposure 2000lxhr], [25 DEG C/relative humidity (RH) 60%/shadings], preserve these detection bodies after 30 days, tested by high performance liquid chromatography (HPLC) and powder x-ray diffraction (XRD).
Powder x-ray diffraction (XRD) measures as mentioned above.
HPLC analyzes, and after the 0.01mol/L dissolving with hydrochloric acid detection bodies 22.9mg of 10mL, carries out the assay of the related substance in crystallization under following condition.
Post Synergi Hydro-RP 80A Phenomenex (Φ 4.6mm × 25cm, 4 μm); Temperature 25 DEG C
Moving phase is dissolving phosphoric acid potassium dihydrogen 2.05g in 3000mL water, adds phosphoric acid and is adjusted to pH3.0.In this liquid 2940mL, add methyl alcohol 60mL modulate.
Flow velocity is about 1.0mL/ minute
Detector Ultravioblet spectrophotometer (measuring wavelength 254nm)
Standard substance 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride
Total related substance refers to the material detected beyond 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride, total related substance (%) for total related substance relative to standard substance containing than.
Table 1 represents the stability result of this test.
The result of stability test is all carried out in the crystallization of I type, the crystallization of II type in various condition (humidification inferior in conditions of exposure), as shown in table 1, do not confirm the increase of total related substance, specifying it is very stable crystal type.
In addition, the crystallization of II type is converted into the crystallization of I type under 40 DEG C/relative humidity (RH) condition of 75%, 30 days, and its fusing point, x-ray diffractogram of powder are consistent with the crystallization of embodiment 1 gained.In addition, above-mentioned type III crystallization is converted into the crystallization of I type by 80 DEG C of heating 2 hours, and its fusing point, x-ray diffractogram of powder are consistent with the crystallization of embodiment 1 gained.
Clear and definite according to above result, the fusing point of I ~ type III crystallization is 192 ~ 197 DEG C, and stability is all very excellent, particularly the crystallization of I type, than the crystallization of II type and type III crystalline stability excellence.
Claims (8)
1. an I type crystallization for 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride, is characterized in that:
There is the x-ray diffractogram of powder shown in Fig. 1, as the diffraction angle recorded by powder x-ray diffraction (2 θ ± 0.1 °), confirm characteristic peak 13.7 °, 15.7 °, 16.0 °, 18.6 °, 20.3 ° and 22.7 °, fusing point is 192 ~ 197 DEG C.
2. I type crystallization as claimed in claim 1, is characterized in that:
It is not containing ethanol.
3. an II type crystallization for 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride, is characterized in that:
Have the x-ray diffractogram of powder shown in Fig. 2, as the diffraction angle recorded by powder x-ray diffraction (2 θ ± 0.1 °), confirm characteristic peak 6.4 °, 12.6 °, 17.3 ° and 21.7 °, fusing point is 192 ~ 196 DEG C.
4. II type crystallization as claimed in claim 3, is characterized in that:
It is not containing ethanol.
5. a medical composition, is characterized in that:
Containing the crystallization according to any one of Claims 1 to 4.
6. an antineoplastic agent, is characterized in that:
Containing the crystallization according to any one of Claims 1 to 4.
7. a manufacture method for the I type crystallization described in claim 1 or 2, is characterized in that:
Heating for dissolving 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride in ethanol, then, is added drop-wise to this lysate in the diethyl ether being cooled to 0 ± 5 DEG C while stir.
8. a manufacture method for the II type crystallization described in claim 3 or 4, is characterized in that:
Heating for dissolving 1-(2 '-cyano group-2 '-deoxidation-β-D-arabinofuranosidase glycosyl) cytosine(Cyt) one hydrochloride or the crystallization of I type, then, after this solution is cooled to 40 ± 5 DEG C, drips diethyl ether and stir in ethanol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0535231A1 (en) * | 1990-06-15 | 1993-04-07 | Sankyo Company Limited | Pyrimidine nucleoside derivative |
| CN1072686A (en) * | 1991-09-30 | 1993-06-02 | 三共株式会社 | Has Pyrmidine nucleoside derivatives of anti-tumor activity and its production and use |
| CN101346132A (en) * | 2005-12-23 | 2009-01-14 | 西克拉塞尔有限公司 | Crystalline pyrimidine nucleoside derivatives suspensions in capsules |
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| US5637688A (en) * | 1994-12-13 | 1997-06-10 | Eli Lilly And Company | Process for preparing 1-(2'-deoxy-2'-difluoro-d-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0535231A1 (en) * | 1990-06-15 | 1993-04-07 | Sankyo Company Limited | Pyrimidine nucleoside derivative |
| CN1072686A (en) * | 1991-09-30 | 1993-06-02 | 三共株式会社 | Has Pyrmidine nucleoside derivatives of anti-tumor activity and its production and use |
| CN101346132A (en) * | 2005-12-23 | 2009-01-14 | 西克拉塞尔有限公司 | Crystalline pyrimidine nucleoside derivatives suspensions in capsules |
Non-Patent Citations (4)
| Title |
|---|
| Atsushi Azuma,等.Nucleosides and Nucleotides. 122. 2"-C-Cyano-2"-deoxy-1-β-D-arabinofuranosylcytosine and Its Derivatives. A new Class of Nucleoside with a Broad Antitumor Spectrum.《J.MED CHEM》.1993,第36卷(第26期),4183-4189. * |
| Atsushi Azuma,等.Nucleosides and Nucleotides. 141. Chemical Stability of a New Antitumor Nucleoside, 2"-C-Cyano-2"-deoxy-1-β-D-arabino-pentofuranosylcytosine in Alkaline Medium: Formation of 2"-C-Cyano-2"-deoxy-l-β-D-ribo-pentofuranosylcytosine and Its Antitumor Activity.《J.MED.CHEM》.1995,第38卷(第17期),3391-3397. * |
| 俞子行.第八章 结晶.《制药化工过程及设备》.中国医药科技出版社,2002,(第2版),223-224. * |
| 权利要求20. * |
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| EP2431376B1 (en) | 2013-08-14 |
| JP6307045B2 (en) | 2018-04-04 |
| WO2010131475A1 (en) | 2010-11-18 |
| KR101414888B1 (en) | 2014-07-03 |
| RU2011146144A (en) | 2013-06-20 |
| DK2431376T4 (en) | 2024-02-26 |
| US20120029182A1 (en) | 2012-02-02 |
| ES2426025T3 (en) | 2013-10-18 |
| EP2431376B2 (en) | 2024-02-07 |
| KR20120022940A (en) | 2012-03-12 |
| HRP20131090T1 (en) | 2013-12-20 |
| FI2431376T4 (en) | 2024-03-13 |
| DK2431376T3 (en) | 2013-09-02 |
| PT2431376E (en) | 2013-09-17 |
| RU2538593C2 (en) | 2015-01-10 |
| JPWO2010131475A1 (en) | 2012-11-01 |
| EP2431376A1 (en) | 2012-03-21 |
| HRP20131090T4 (en) | 2024-03-15 |
| EP2431376A4 (en) | 2012-08-01 |
| JP5801715B2 (en) | 2015-10-28 |
| PL2431376T3 (en) | 2014-01-31 |
| JP2015157867A (en) | 2015-09-03 |
| US8377905B2 (en) | 2013-02-19 |
| CN102414216A (en) | 2012-04-11 |
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